Artículo
Development of new 1, 3-dihydroxyacridone derivatives as Akt pathway inhibitors in skeletal muscle cells
Irazoqui, Ana Paula
; Menéndez, Cintia Anabella
; Steingruber, Sebastián; González, Agustina
; Appignanesi, Gustavo Adrian
; Buitrago, Claudia Graciela
; Gerbino, Darío César
Fecha de publicación:
31/10/2022
Editorial:
Academic Press Inc Elsevier Science
Revista:
Bioorganic Chemistry
ISSN:
0045-2068
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
In the present work, four new compounds based on the privileged structure acridone were efficiently synthesized following simple operational techniques and biologically tested on proliferative skeletal muscle cells (C2C12) and rhabdomyosarcoma cells (RD) showing no significant changes in the number of dead or viable cells at 1 µM during 24 or 48 h of treatment. Of relevance, acridone derivatives 3a-3d at 0.5 µM for 24 h effectively inhibited Akt activation in C2C12, while at 1 µM only compounds 3a and 3b have effect. RD cells showed a different response pattern. These cells treated with 3a (0.5 µM), 3b (0.5 µM) or 3d (0.5 or 1 µM) for 24 h shown significant Akt inhibition. In addition, 3a-3d assayed at 1 µM for 48 h were highly successful in inhibiting Akt phosphorylation. Finally, based on molecular docking and molecular dynamics simulations, we rationalize the experimental results mentioned above and propose that 3-phosphoinositide-dependent kinase-1 (PDK1) could be one of the molecular targets of this new series of 1, 3-dihydroxyacridone derivatives. Biological and in silico studies revealed that 3b could be considered as the most promising prototype for the development of new antitumor agents.
Palabras clave:
ACRIDONES
,
AKT PATHWAY INHIBITORS
,
SKELETAL MUSCLE CELLS
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Colecciones
Articulos(INBIOSUR)
Articulos de INSTITUTO DE CIENCIAS BIOLOGICAS Y BIOMEDICAS DEL SUR
Articulos de INSTITUTO DE CIENCIAS BIOLOGICAS Y BIOMEDICAS DEL SUR
Citación
Irazoqui, Ana Paula; Menéndez, Cintia Anabella; Steingruber, Sebastián; González, Agustina; Appignanesi, Gustavo Adrian; et al.; Development of new 1, 3-dihydroxyacridone derivatives as Akt pathway inhibitors in skeletal muscle cells; Academic Press Inc Elsevier Science; Bioorganic Chemistry; 130; 31-10-2022; 1 - 11
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